Genetics of REM Sleep Behavior Disorder

et al. 2020

Preprint

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Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is a parasomnia, characterized by loss of muscle atonia and dream enactment occurring during REM sleep phase. Since a large subgroup of iRBD patients will convert to Parkinson s disease, and since previous genetic studies have suggested common genes, it is likely that there is at least a partial overlap between iRBD and Parkinson s disease genetics. To further examine this potential overlap and to identify genes specifically involved in iRBD, we fully sequenced 25 genes previously identified in genome-wide association studies of Parkinson s disease. The genes were captured and sequenced using targeted next-generation sequencing in a total of 1,039 iRBD patients and 1,852 controls of European ancestry. The role of rare heterozygous variants in these genes was examined using burden tests and optimized sequence Kernel association tests (SKAT-O), adjusted for age and sex. The contribution of biallelic (homozygous and compound heterozygous) variants was further tested in all genes. To examine the association of common variants in the target genes, we used logistic regression adjusted for age and sex. We found a significant association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage ≥50X and 0.0004 at ≥30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in a total of 22 (1.2%) controls vs. two (0.2%) patients. Rare non-coding heterozygous variants in LAMP3 were also found to be associated with reduced iRBD risk (p=0.0006 at ≥30X). We found no statistically significant association between rare heterozygous variants in the rest of genes and risk of iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD patients vs. controls. To examine the potential impact of the rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. All three variants seem to be loss-of-function variants significantly affecting the protein structure and stability. Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD, and additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 97%

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Novel associations of BST1 and LAMP3 with rapid eye movement sleep behavior disorder

Mufti

et al. 2020

Preprint

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“…1,2 While our understanding of the genetic background of DLB or MSA is limited, there are 80 genetic loci found to be associated with PD risk discovered through genome-wide association studies (GWASs), 3,4 and several genes have been implicated in familial PD. [5][6][7] Recent studies have suggested that there is some overlap between the genetic backgrounds of iRBD and PD or DLB, yet this overlap is only partial. GBA variants are associated with iRBD risk, PD and DLB, 5,8 but pathogenic LRRK2 variants are only associated with PD, and not with iRBD and DLB.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Recent studies have suggested that there is some overlap between the genetic backgrounds of iRBD and PD or DLB, yet this overlap is only partial. GBA variants are associated with iRBD risk, PD and DLB, 5,8 but pathogenic LRRK2 variants are only associated with PD, and not with iRBD and DLB. 7,9,10 MAPT and APOE haplotypes are important risk factors of PD and DLB, respectively, 11,12 but neither are linked to iRBD.…”

Section: Introductionmentioning

confidence: 99%

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder

Mufti¹,

et al. 2021

Neurology

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Objective:To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).Methods:We fully sequenced 25 genes previously identified in GWASs of PD, in a total of 1,039 iRBD patients and 1,852 controls. The role of rare heterozygous variants in these genes was examined using burden tests. The contribution of biallelic variants was further tested. To examine the potential impact of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.Results:We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in 22 (1.2%) controls vs. two (0.2%) patients. All three variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare non-coding heterozygous variants in LAMP3 were also associated with iRBD (p=0.0006 at >30X). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.Conclusion:Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.

A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

Mufti

et al. 2020

Preprint

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Objective: To examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD). Methods: Ten genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth. Results: We found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls. Conclusion: Our results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.